Hyaluronic acid and chondroitin sulphate play an important role in the biological organism, especially as a main component of the intercellular matrix and mechanical support for many kinds of cells, such as those of the skin, tendons, muscles and cartilage. Hyaluronic acid and chondroitin sulphate also play other important parts in biological processes, such as the moistening of tissues, lubrication and mechanical loading.
Water soluble gel forming materials comprising hyaluronic acid or salts thereof are well-known and widely used in the health care sector, for example in ophthalmology, in the treatment of osteoarthritis, as well as in the pharmaceutical and cosmetics industries.
A number of chondroitin sulphate/hyaluronate compositions are known as viscous or viscoelastic agents for ophthalmic surgical use. Due to their particular physical characteristics, certain viscoelastic agents will be better suited for particular aspects of the surgical procedure. For example, in cataract surgery, it is commonly used the combination of relatively low molecular weight sodium hyaluronate and chondroitin sulphate. However, high molecular weight agents tend to be highly cohesive and, in general, very viscous solutions containing relatively high molecular weight agents, including high molecular weight sodium hyaluronate, are more effective in maintaining the intraocular space than less viscous solutions containing relatively lower molecular weight agents.
Viscoat (Alcon Laboratories, Inc.) is a viscoelastic solution which contains about 3% sodium hyaluronate and 4% chondroitin sulphate in a physiological buffer with a viscosity of 40,000±20,000 cps (at shear rate of 2 see and 25° C.), wherein the sodium hyaluronate used has a molecular weigh of 500,000 Daltons.
US 2011/0015151 discloses aqueous viscoelastic compositions for use in ophthalmic surgical procedures, comprising a combination of hyaluronic acid and chondroitin sulphate, wherein the hyaluronic acid has a molecular weight of 1,500,000 to 1,900,000 Daltons and is present at a concentration of 1.7% w/v. The chondroitin sulphate or ophthalmically acceptable salt thereof used has a molecular weight of 20,000 to 100,000 Daltons and is present at a concentration of 4% w/v.
Viscoelastic compositions have been also used in other surgical procedures, U.S. Pat. No. 6,632,423 describes a viscoelastic agent characterized by a viscosity of at least 30 Pa·s, comprising sodium hyaluronate and chondroitin sulphate, which is used as a packing material in middle ear surgery. The sodium hyaluronate has an average molecular weight of about 2.2 million Daltons and is present at a concentration of about 1.6% by weight. The chondroitin sulphate used has an average molecular weight of about 50,000 Daltons and is present at a concentration of about 4% by weight.
Less viscous sodium chondroitin sulphate/hyaluronate mixtures are suitable for other uses, such as the treatment of osteoarthritis, wherein the molecular weight of sodium hyaluronate is usually less than 1,000,000 daltons. A conventional treatment of osteoarthritis involves the intra-articular application of hyaluronate or chondroitin sulphate/hyaluronate mixtures. However, the effect of this treatment with conventional hyaluronate is usually temporal because the hyaluronate remains within the articular chamber for short time before it is absorbed and/or metabolized.
WO 03/041724 reveals intra-articular application of a mixture of 30 mg/mL sodium hyaluronate and 40 mg/mL sodium chondroitin sulphate for the management of osteochondral lesions of the knee inductor of chondrogenesis, to regenerate the cartilage destroyed by osteoarthritis. The sodium hyaluronate has a molecular weight of 500,000 to 1,000,000 Daltons, and the composition disclosed therein has a viscosity of 20,000 to 60,000 m·Pas (cps).
WO 2009/138843 discloses a glycosaminoglycan oral composition comprising (a) from 80 mg to 200 mg of hyaluronic acid or a pharmaceutically acceptable salt thereof having an average molecular weight of not less than 10,000 Daltons; and (b) from 150 mg to 500 mg of chondroitin sulphate or a pharmaceutically acceptable salt thereof having an average molecular weight of from 5,000 to 50,000 Daltons; in a mixture with a pharmaceutical carrier.
Furthermore. EP0136782 discloses an aqueous composition containing chondroitin sulphate and sodium hyaluronate for use as an active therapeutic material. The chondroitin sulphate/sodium hyaluronate solution is prepared in a buffer containing 5.3 g of chondroitin sulphate and 4.2 g of sodium hyaluronate in 100 mL of water, which has a viscosity at 25° C. 71,500 mPa·s.
Interestingly, addition of chondroitin sulphate to sodium hyaluronate in aqueous solution dramatically increases the viscosity of mixture (Nishimura et al., Biochimica et Biothphysica Acta 1380, 1-9 (1998)). This increase in viscosity appears to be mainly due to the increase in molecular weight rather than solute concentration increase.
Chondroitin sulphate has interesting biological properties for the treatment of joints and bones. The administration of exogenous chondroitin sulphate can enhance the production of newly synthesized ECM components, endogenous hyaluronic acid and proteoglycans (J. Y. Reginster et al., Drugs aging 24(7), 573-580, (2007)). It may suppress the production and activity of proinflammatory mediators and proteases, and there is evidence showing that chondroitin sulphate prevents the degradation of cartilage and may promote its regeneration (J. Y. Reginster at al., Mini Rev. Med. 7(10), 1051-1061 (2007) and Wildi at al., Ann. Rheum. Dis. 70(6), 982-989 (2011)).
Synovial fluid is primarily composed of high molecular weight sodium hyaluronate, the concentration of sodium hyaluronate in the normal human synovial joint fluid is approximately 3 mg/mL. In osteoarthritis patients, the concentration and molecular weight of sodium hyaluronate in synovial fluid decrease, resulting in the diminished capacity of the fluids to protect the cartilage. Additionally, high molecular weight hyaluronic acid formulations stimulate the synthesis of hyaluronic acid more than lower molecular weight formulations (M M. Smith et al., Rheumatol. Int. 7(3), 113-22 (1987)), reduce the production and activity of proinflammatory mediators and matrix metalloproteinases and maintains joints in good condition (H. Matsuno, et al., Inflamm. Res. 48, 154-159 (1999), M. Goto et al., Clin. Exp. Rheumatol 19, 377-383 (2001) and L. Morelans et al., Arthritis Res. Ther. 5, 54-67 (2003)).
Therefore, more concentrated mixtures or formulations comprising high molecular weights sodium hyaluronates are expected to be more effective but also highly viscous and consequently unsuitable for some routes of administration or applications such as intra-articular injection. For example, current formulations for the treatment of osteoarthritis are generally administered at 2 to 6 doses over 1 to 3 months at 7-20 day intervals in order to reach an acceptable therapeutic effect. The main reported adverse event of this treatment is pain in the injection site, caused mainly by the high viscosity of the formulations injected. This problem inevitably limits the molecular weight of the hyaluronic acid used and/or the quantity of hyaluronic acid and chondroitin sulphate to be injected.
In view of the above, there is still a need to develop new pharmaceutical compositions comprising hyaluronic acid and chondroitin sulphate, exhibiting a lower viscosity while maintaining their known therapeutically effects, thus allowing an improvement in the treatment of patients.